Mitosis is a cell division process involving a series of cell cycle events in which the nucleus of a cell divides to form two new nuclei, each of which contains a complete copy of the parental chromosomes. The two nuclei ultimately become disconnected and constitute mother and daughter nuclei.
Coordinated execution of cell cycle events is essential for orderly progression through the division cycle and for the maintenance of genome integrity [1]. Any gross departure from this coordination leads to genomic instability associated with many human cancers.
It is known that cellular coordination is imposed, in part, by stress response pathways known as checkpoint controls which ensure that, if a certain event is either interrupted or executed erroneously, the subsequent phase of the cell cycle is not initiated.
During S phase, the genome integrity is mainly monitored by the DNA replication checkpoint [2]. The task of the replication checkpoint is to sense incomplete DNA replication and to respond by delaying the mitotic programme [7]. The Replication Checkpoint also helps maintain stalled replication forks in a state that permits them to resume DNA synthesis [3].
In yeast, Mec1 (homologous to human ATM/ATR kinases) and Rad53 (homologous to human Chk2 kinase) proteins are critical effectors of the replication checkpoint. Like in yeast, phosphoinositide 3-kinase related kinases (PIKKs) ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3-related) are important stress response regulators during S phase in mammalian cells.
Although the DNA replication checkpoint is known to delay mitosis in response to replication blocks, the molecular mechanisms underlying this mitotic restraint have been relatively ill defined. Recently it has been demonstrated that budding yeast cells avoid mitosis during S phase by repressing the accumulation of the anaphase promoting complex activator, APC Cdc20 [4].
Agents that are capable of interrupting the mitotic programme of targeted cells can be used to initiate cell cycle arrest and/or apoptosis (programmed cell death). Such agents may be used as therapeutic agents for treating conditions associated with the targeted cells.
Normal cells have several checkpoint pathways designed to cope with genotoxic stress that can lead to chromosomal abnormalities. Mutations in cancer cells frequently render them ineffective in order to provide them with proliferative advantage. Cells defective in these pathways are often sensitive to agents that cause genotoxic stress. Such agents may be used as antiproliferation agents to abrogate, inhibit or prevent cell proliferation of cancer cells.